Haemochromatosis diagnostic tests

Two-step strategy

A two-step test strategy: biochemical iron overload first, then establish the cause
*The mistake is testing ferritin alone* - ferritin is an acute phase reactant, and most raised ferritin in Australia is alcohol, MASLD, inflammation or malignancy, not haemochromatosis

C282Y homozygosity ~1 in 200 of northern European ancestry; carrier ~1 in 8-10
Penetrance is low: only ~25-30% of male and ~1-10% of female homozygotes develop clinical disease
Raised ferritin is found in ~5-10% of routine panels - only a small fraction is haemochromatosis
*Population screening is NOT recommended - cascade testing of first-degree relatives is*

Hepcidin deficiency -> ferroportin remains open -> unregulated intestinal absorption
Transferrin saturates first (hence transferrin saturation is the earliest abnormality), then ferritin rises as stores fill
- -> the sequence explains why a young homozygote can have a high saturation with a normal ferritin
Non-transferrin-bound iron -> hepatocyte, myocyte, beta cell and pituitary uptake -> free radical injury
Parenchymal (hereditary) vs reticuloendothelial (transfusional) distribution - visible on MRI and biopsy

Test	Haemochromatosis	Note
Transferrin saturation	>45% (F) / >50% (M)	*The most sensitive early marker*; fasting sample
Ferritin	Raised, often >1000 microg/L	Reflects stores; acute phase reactant
Transferrin / TIBC	Low-normal
Serum iron	Raised	Diurnal variation - unreliable alone

*Both raised -> pursue. Ferritin raised with a NORMAL saturation -> look elsewhere*
Repeat fasting before acting - a single abnormal result is often transient

Differential of a raised ferritin with NORMAL transferrin saturation

Alcohol, MASLD/metabolic syndrome (the commonest cause by far)
Inflammation, infection, malignancy (check CRP)
Haemophagocytic lymphohistiocytosis (ferritin often >10,000), adult-onset Still disease
Cell lysis - hepatitis, haemolysis, rhabdomyolysis
Ferroportin disease (type 4) - macrophage loading, autosomal dominant

Genotype	Interpretation
C282Y homozygote	Confirms hereditary haemochromatosis (~90% of cases)
C282Y/H63D compound heterozygote	Rarely causes overload alone - look for a cofactor (alcohol, MASLD, hepatitis)
H63D homozygote or simple heterozygote	*NOT a cause of significant iron overload* - if overload is real, investigate other causes
Wild type with genuine overload	Non-HFE (HJV, HAMP, TFR2, SLC40A1), or secondary

Genetic counselling before testing; implications for relatives and, in some jurisdictions historically, insurance

*MRI (T2/R2, "FerriScan") to quantify hepatic iron concentration* - has largely replaced biopsy*
*Cardiac T2 MRI** if cardiac loading suspected (especially transfusional overload)
Liver biopsy - now reserved for staging fibrosis where the risk of cirrhosis is significant, or where the diagnosis remains unclear
- Indications: ferritin >1000 microg/L, raised ALT, or hepatomegaly - below all three, cirrhosis is very unlikely and biopsy can be avoided
- Perls Prussian blue; hepatic iron index (micromol/g dry weight / age) >1.9
Non-invasive fibrosis: FIB-4, transient elastography

Fasting glucose / OGTT and HbA1c - HbA1c may be falsely low with venesection-driven red cell turnover
Pituitary function, especially gonadotrophins - LH, FSH, testosterone/oestradiol; TFTs
ECG; echocardiogram if cardiomyopathy suspected
LFTs, INR, albumin; AFP + liver ultrasound if cirrhotic
DEXA - hypogonadal osteoporosis
Joint X-rays if arthropathy (2nd/3rd MCP, chondrocalcinosis)

inc Red cell turnover or transfusion dependence: thalassaemia, sickle cell disease, sideroblastic anaemia, myelodysplasia, chronic haemolysis
Also: repeated transfusion for any cause, excessive parenteral iron, porphyria cutanea tarda, African iron overload

Confirmed C282Y homozygote with iron overload -> venesection to ferritin <50 microg/L, then maintenance 50-100
C282Y homozygote with NORMAL iron studies -> no treatment; monitor iron studies 1-2 yearly
Ferritin >1000 or raised ALT or hepatomegaly -> stage the liver (biopsy or elastography); if cirrhotic, lifelong 6-monthly ultrasound for HCC, regardless of subsequent iron depletion
Secondary overload, transfusion-dependent -> *chelation, not venesection - deferasirox* (oral), desferrioxamine, deferiprone
Raised ferritin, normal saturation, no genotype -> treat the alcohol, the metabolic syndrome or the inflammation; do not venesect

First-degree relatives (adults): transferrin saturation, ferritin AND HFE genotype
Test the PARTNER rather than the children of a homozygote - children are obligate heterozygotes; they are only at risk if the other parent carries C282Y

Hb before each venesection; ferritin every 2-3 venesections during induction, then 3-6 monthly
Do not chase the transferrin saturation during induction - it stays high until stores are depleted

Diabetes, hypogonadotrophic hypogonadism, hypothyroidism, osteoporosis
Cardiomyopathy (dilated then restrictive), arrhythmia, conduction disease
Arthropathy of the 2nd/3rd MCPs; chondrocalcinosis/pseudogout
Hepatocellular carcinoma, cirrhosis
Porphyria cutanea tarda - HFE mutations over-represented
Thalassaemia, sickle cell disease, sideroblastic anaemia, MDS - secondary overload
**Vibrio vulnificus, Yersinia enterocolitica, Listeria** - siderophilic infection
Alcohol, MASLD, hepatitis B/C - cofactors that raise both ferritin and the risk of fibrosis

A C282Y homozygote with normal iron studies may never develop disease - penetrance, not genotype, determines outcome
Ferritin <1000 microg/L with normal ALT and no hepatomegaly -> cirrhosis very unlikely
Diagnosis before cirrhosis and diabetes -> normal life expectancy; after cirrhosis, survival falls markedly
HCC risk persists after successful iron depletion if cirrhosis was established - surveillance is lifelong
Iron studies should be repeated 1-2 yearly in untreated homozygotes and C282Y/H63D compound heterozygotes

13 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.